Tetramethylalkane derivatives

ABSTRACT

2,2,9,9-Tetramethyldecanedial, 2,2,9,9-Tetramethyldecanedial disemicarbazone and di(trialkylsilyl)-derivative of 2,2,9,9tetramethyl-1,10-decanediol are disclosed. The compounds lower serum triglyceride levels. The aldehyde can be produced by hydrolysis of a substituted imine. The aldehyde can be converted to semicarbazone derivatives by reaction with semicarbazide or its acid-addition salt. The trialkylsilyl compounds can be produced by reacting 2,2,9,9-tetramethyl-1,10-decanediol with a silylating agent.

United States Patent Moersch et al.

[ 51 Dec. 30, 1975 I TETRAMETHYLALKANE DERIVATIVES [75] Inventors: George W. Moersch; Paul L. Creger,

both of Ann Arbor, Mich.

[73] Assignee: Parke, Davis & Company, Detroit,

Mich.

22 Filed: Sept. 20, 1974 21 Appl. No.: 507,633

Related US. Application Data [62] Division of Ser. No. 327,977, Jan. 30, 1973, Pat. No. 3,857,884, which is a division of Ser. No. 29,704, April 17, 1970, Pat. No. 3,742,068.

OTHER PUBLICATIONS Kossa nyi; Chem. Abs., Vol. 63 (1965), p. 483b.

pounds Petrov et al., Zhun 30,ll0730,l 117, (1960).

Kossanvi, Chem. Abs., Vol. 54, p. 24359(d).

Obshckeikhim, pp.

Primary Examiner.lames 0. Thomas, Jr. Assistant ExaminerR. H. Liles [57] ABSTRACT 2,2,9,9-Tetramethyldecanedial, 2,2,9,9-Tetramethyldecanedial disemicarbazone and di(trialkylsilyl)- derivative of 2,2,9,9-tetramethyI-l ,IO-decanediol are disclosed. The compounds lower serum triglyceride levels. The aldehyde can be produced by hydrolysis of a substituted imine. The aldehyde can be converted to semicarbazone derivatives by reaction with semicarba zide or its acid-addition salt. The trialkylsilyl comcan be produced by reacting 2,29,9- tetramethyl-l lO-decanediol with a silylating agent.

7 1 Claim, No Drawings 'TETRAMETHYLALKANE DERIVATIVES This application is a divisional application of application Ser. No. 327,977, filed Jan. 30, 1973 now US. Pat. No. 3,857,884 which is a divisional application of ap- 5 plication Ser. No. 29,704, filed Apr. 17, 1970, now US. Pat. No. 3,742,068.

SUMMARY AND DETAILED DESCRIPTION The present invention relates to new polymethylene compounds. More particularly, the invention relates to new functionally-substituted tetramethylpolymethylene compounds of the formula In this formula W can represent (a) a group of the formula In accordance with'the invention, the disilylated compounds of the invention, that is, the compounds wherein W represents wherein each of R and R represents methyl or ethyl, can be produced by reacting 2,2,9,9-tetramethyl-l ,10- decanediol with a silylating agent in an anhydrous, non-hydroxylic solvent. Some examples of suitable silylating agents are hexaalkyldisilazanes, N,O-bis(- trialkylsilyl)acetamides, N-trialkylsilyl-acetamides, N- (trialkylsilyl)dialkylamines, and trialkylchlorosilanes in the presence of a tertiary amine such as pyridine. The preferred silylating agents are hexaalkyldisilazanes of the formula in which R and R are as defined before. Some examples of such hexaalkyldisilazanes are hexamethyldisila- Zane, hexaethyldisilazane, 1,3-diethyl-l,1,3 ,3-tetramethyldisilazane, and 1 ,l,3,3-tetraethyl-1,3-dimethy1- disilazane. Some examples of suitable anhydrous, nonhydroxylic solvents are hydrocarbons such as benzene, toluene, xylene, and cyclohexane; chlorinated hydrocarbons such as chloroform, carbon tetrachloride, and chlorobenzene; ethers such as dioxane, tetrahydrofuran, dimethoxyethane, dibutyl ether, and diethylene glycol dimethyl ether; or an excess of the disilazane used as a reactant. Some preferred solvents are toluene or excess disilazane reactant. The hexaalkyldisilazanes which are the preferred silylating agents, as indicated above, are most suitably used in the presence of an anhydrous acidic catalyst. Some examples of such catalysts are ammonium sulfate, ammonium chloride, ammonium bromide, ammonium dihydrogen phosphate, hydrogen chloride, hydrogen bromide, hydrocarbon sulfonic acids, and cation exchange resins in the hydrogen ion form. The anhydrous acidic catalyst can also be generated in situ, as by forming hydrogen chloride by adding a trace amount of a trialkylchlorosilane to the reaction mixture. At least the calculated amount and preferably an excess of the silylating agent is employed. The time and temperature of the reaction are not particularly critical but they depend somewhat on the particular silylating agent. In general, it is suitable to carry out the reaction at a temperature from 0 to 175C. or the reflux temperature of the solvent for from 30 minutes to 18 hours. In the case of the hexaalkyldisilazanes, the usual conditions are room temperature to C. for up to 18 hours. In most cases, a reaction time of 1 hour at room temperature is sufficient.

The 2,2,9,9-tetramethyl-1,lO-decanediol, employed as starting material in the foregoing process, can be prepared by any of a variety of methods. For example, it can be obtained by reducing 2,2,9,9-tetramethyldecanedioic acid or a lower alkyl ester thereof. The reduction is usually carried out by reacting the acid or ester with a complex metal hydride such as lithium aluminum hydride, lithium aluminum hydridealuminum chloride, aluminum hydride-aluminum chloride, or sodium borohydride-aluminum chloride in an anhydrous ethereal solvent, followed by hydrolyzing the reaction mixture. In the case of reduction of a lower alkyl ester, other reducing agents can also be used such as sodium borohydride in aqueous ethanol.

Further in accordance with the invention, the aldehyde of the invention, that is, the compound wherein W represents in which X represents oxo, said compound being 2,2,9,9-tetramethyldecanedial, can be produced by reacting a compound of the formula with a hydrolytic agent; where R represents a hydrocarbon radical or substituted hydrocarbon radical of not more than carbon atoms. Some examples of hydrocarbon radicals which R can represent are methyl, ethyl, isopropyl, butyl, tertiary butyl, hexyl, decyl, cyclopentyl, cyclohexyl, and methylcyclohexyl. When R represents a substituted hydrocarbon radical the nature and number of substitutents are unimportant as the group R is lost during the course of the reaction. A preferred example of R is cyclohexyl. Some examples of suitable hydrolytic agents are water, aqueous solutions of mineral acids such as hydrochloric acid, phosphoric acid, or sulfuric acid, and aqueous solutions of organic acids such as acetic acid or p-toluenesulfonic acid. If desired, an organic solvent such as tetrahydrofuran, a lower alkanol, or a lower alkanone can also be present. A preferred hydrolytic agent is aqueous hydrochloric acid optionally in the presence of tetrahydrofuran or other organic solvent. At least the calculated amount and preferably a large excess of the hydrolytic agent is used. The time and temperature of the reaction are not especially critical. In general, the reaction is carried out at a temperature from 0 to 125C. or the reflux temperature for from 1 hour to 24 hours, the longer reaction times being used at the lower temperatures. At a temperature of about 3035C. with dilute hydrochloric acid, the reaction is normally substantially complete within less than 24 hours.

Starting materials required for use in the foregoing process can be prepared in any of a number of ways. For example, an imine of the formula in which X represents semicarbazono, can be produced by reacting a compound of the formula with semicarbazide or an acid-addition salt thereof.

The reaction can be carried out under acidic, neutral, or slightly basic conditions. However, the use of moderately acidic conditions (pl-l about 4.5) is preferred. Some suitable solvents for use in the reaction are lower alkanols and aqueous lower alkanols. Hydrocarbons capable of forming azeotropic mixtures with the water formed in the reaction are also suitable solvents. A preferred solvent is aqueous ethanol. Two moles of semicarbazide or acid-addition salt are theoretically necessary for reaction with each mole of the aldehyde employed as starting material and, in practice, it is customary to use a quantity of semicarbazide or acidaddition salt in excess of the calculated amount. A preferred reactant is semicarbazide hydrochloride. The time and temperature of the reaction are not especially critical. In general, the reaction is carried out at a temperature from 20 to 1 15 C. or the reflux temperature of the solvent for from 30 minutes to 24 hours. At temperatures of 50 to C., the reaction is normally substantially complete within less than 1 hour.

The compounds of the invention can exist in anhydrous form as well as in solvated, including in some cases hydrated, forms. In general, the hydrated forms and the solvated forms with pharmaceutically-acceptable solvents are equivalent to the anhydrous or unsolvated form for the purposes of the invention.

The compounds of the invention are new chemical substances, of value as pharmacological agents which reduce serum triglyceride levels. An important property of these compounds is that they reduce serum triglyceride levels while causing only a lesser reduction and in some cases no reduction in serum cholesterol levels. The effectiveness of the compounds of the invention in lowering serum triglycerides can be demonstrated by standard methods. For example, male rats weighing 200-250 g. are maintained on a normal pellet diet. Each animal in a treatment group is given a daily oral dose of a test compound for 7 days. Commonly a test compound is first studied at a daily dose of 250 mg./kg. body weight; in subsequent groups of rats, the dose is progressively lowered until the compound no longer exhibits significant activity. An untreated control group is also maintained. At the end of the 7-day test period the animals are weighed and sacrificed, and the serum cholesterol and serum triglycerides are determined from blood samples taken from the vena cava. The methods used are described in Journal of Laboratory and Clinical Medicine, 50, 318 (1957) and Journal of Laboratory and Clinical Medicine", 50, 1 52 (1957). The test compound is considered to exhibit a side effect if the weight of the animals in the treatment group is significantly less than the weight of the animals in the control group. In a determination, the following preferred compound of the invention at the indicated daily dose levels for 7 days produced the indicated reduction of serum triglycerides, reduction of serum cholesterol, and weight gain inhibition relative to the untreated control group. 2,2,9,9-Tetramethyldecanedial, 100 mg./kg. per day; 87% reduction of serum triglycerides; 28% reduction of serum cholesterol; 20% weight gain inhibition. In addition to administration by the oral route, as described above, the compounds of the invention can also be given by the parenteral route if desired.

The invention is illustrated by the following examples.

EXAMPLE 1 A mixture of 11.5 g of 2,2,9,9-tetramethyl-1,10- decanediol, 20 g. of hexamethyldisilazane, and 0.2 g. of trimethylchlorosilane in a small amount of toluene is heated to 90-100C. until a solution results. A small amount of insoluble white solid which may be present is ignored. The mixture is allowed to cool and stand at room temperature for 18 hours and is filtered. The filtrate is distilled in vacuo to give 2,2,5,5,l2,12,15,loctamethyl-3 ,1 4-dioxa-2,l 5 -disilahexadecane; b.p. 94-98 C. at 0.01 mm.

The starting material can be obtained as follows. With stirring at room temperature, 25.8 g. of 2,2,9,9- tetramethyldecanedioic acid in 175 ml. of dry tetrahydrofuran is added over a period of 20 minutes to a slurry of 8.6 g. of lithium aluminum hydride and 400 ml. of dry ether. The mixture is heated at reflux for 2 hours, treated successively with 8.6 ml. of water, 8.6 ml. of sodium hydroxide solution, and 17.2 ml. of water, and filtered. The filtrate is concentrated to a small volume to give 2,2,9,9-tetramethyl-l,10- decanediol; m.p. 6l62 C. following crystallization from acetonitrile.

EXAMPLE 2 tained. One hour later the mixture is allowed to warm to room temperature and stirred for 18 hours. At this point, the mixture contains N,N'-(2,2,9,9-tetramethyldecanediylidene)-biscyclohexylamine. It is stirred with 400 ml. of 2 N hydrochloric acid for 24 hours at 303 5 C. The organic phase is separated, washed with 100 ml. of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure to give a residue of 2,2,9,9-tetramethyldecanedial. For purification, the product is distilled in vacuo; b.p. 1 l21 13 C. at 1.0 mm.

EXAMPLE 3 A solution of 11.3 g. of 2,2,9,9-tetramethyldecanedial in 60 ml. of ethanol is treated at 50 C. with 12.3 g. of semicarbazide hydrochloride and then with a solution of 9.0 g. of sodium acetate in 120 ml. of 50% methanol. The mixture is heated at reflux for 1 hour, diluted with 120 ml. of 50% aqueous ethanol, and chilled until separation of product appears complete. The product is collected on a filter and washed with cold 50% aqueous ethanol. It is 2,2,9,9-tetramethyldecanedial, disemicarbazone; m.p. l99200 C. following crystallization from ethanol.

We claim:

1. The compound 2,2,9,9-tetramethyldecanedial. 

1. THE COMPOUND 2,2,9,9-TETRAMETHYLDECANEDIAL. 